Despite intensive effort to discover drugs that may be of value in the systemic treatment of human immuno-deficiency virus (HIV) infections, such infections have been singularly resistant to chemotherapy. The intra-cellular and intimate relation to nuclear metabolism of virus reproduction makes it difficult to destroy a virus without irreparable damage to the host cell.
The discovery of the antiviral activity of vidara-bine (9-.beta.-D-arabinofuranosyladenine monohydrate) has led to the preparation of a large number of synthetic nucleosides. To date, only one synthetic nucleoside, 3'-azido-3'-deoxy-thymidine has been approved for treating certain AIDS patients, but it is a palliative, not a cure. ##STR2##
Although AZT is specifically active against retro-viruses, its use has led to side effects, including anemia, headache, confusion, anxiety, nausea and insomnia. The nucleoside analog, 2',3'-dideoxycytidine (DDC), exhibits an in vitro TI.sub.50 of ca. 300 against HIV and may exhibit fewer side effects than AZT, but may also be eliminated more rapidly from the body. ##STR3## The synthesis of adenine ("6-amino-purine") nucleoside analogs in which the pentose sugar has been replaced with tris(hydroxy)-substituted cyclopentyl residues has yielded compounds with substantial cytotoxic and antiviral activity. For example, the carbocyclic analog of vidarabine, cyclaridine, is highly active against HSV-2, but exhibits a low therapeutic index (TI.sub.50 =10) against HIV in vitro. Likewise, the carbocyclic analog of AZT is inactive against HIV. Therefore, it is clear that the structure-activity relationships between the variously substituted carbocyclic nucleosides which have been prepared and tested remain ill-defined.
Thus, a substantial need exists for chemotherapeutic agents effective to protect mammalian cells against infection by viruses such as HSV-2, HIV, varicella-zoster, vaccinia, human cytomegalovirus (HCMV) and the like.